2Department of Physiology, University of Toronto, Toronto, Ontario, Canada

3Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Abstract

Acute elevations of plasma free fatty acid (FFA) levels augment glucose-stimulated insulin secretion (GSIS). Prolonged elevations
of FFA levels reportedly impair GSIS, but no one has previously compared GSIS after prolonged exposure to saturated or unsaturated
fat. Rats received a low-fat diet (Low-Fat) or one enriched with either saturated (Lard) or unsaturated fat (Soy) for 4 weeks.
Insulin responses during hyperglycemic clamps were augmented by saturated but not unsaturated fat (580 ± 25, 325 ± 30, and
380 ± 50 pmol · l−1 · min−1 in Lard, Soy, and Low-Fat groups, respectively). Despite hyperinsulinemia, the amount of glucose infused was lower in the
Lard compared with the Low-Fat group. Separate studies measured GSIS from the perfused pancreas. Without fatty acids in the
perfusate, insulin output in the Lard group (135 ± 22 ng/30 min) matched that of Low-Fat rats (115 ± 13 ng/30 min), but exceeded
that of Soy rats (80 ± 7 ng/30 min). When FFAs in the perfusate mimicked the quantity and composition of plasma FFAs in intact
animals, in vivo insulin secretory patterns were restored. Because the GSIS of rats consuming Lard diets consistently exceeded
that of the Soy group, we also assessed responses after 48-h infusions of lard or soy oil. Again, lard oil exhibited greater
insulinotropic potency. These data indicate that prolonged exposure to saturated fat enhances GSIS (but this does not entirely
compensate for insulin resistance), whereas unsaturated fat, given in the diet or by infusion, impairs GSIS. Inferences regarding
the impact of fatty acids on GSIS that are based on models using unsaturated fat may not reflect the effects of saturated
fat.